2-position ketals of a-norandrostanes and derivatives thereof

ABSTRACT

THIS INVENTION RELATES TO NEW 2-KETAL DERIVATIVES OF ANORANDROSTANE WHICH ARE USEFUL IN THE PREPARATION OF CYANO-CONTAINING ANDROSTANCES HAVING FERTILITY INHIBITING ACTIVITY.

United States Patent 3,647,820 Z-POSITION KETALS 0F A-NORANDROSTANES 1 AND DERIVATIVES THEREOF Seymour D. Levine, North Brunswick, and Patrick A. Diassi, Westfield, N.J., assignors to E. R. Squibb.& Sons, Inc., New York, N.Y.

No Drawing. Continuation-impart of application Ser. N 0.

792,235, Jan. 16, 1969, which is a division of application Ser. No. 621,755, Mar. 9, 1967, now Patent No. 3,468,955, which in turn is a division of application Ser. No. 440,311, Mar. 16, 1965, now Patent No. 3,330,851. This application Apr. 13, 1970, Ser. No. 28,046

Int. Cl. C07d 13/04 US. Cl. 260-3403 9 Claims ABSTRACT OF THE DISCLOSURE This invention relates to new 2-ketal derivatives of A- norandrostane which are useful in the preparation of cyano-containing androstanes having fertility inhibiting activity.

This application is a continuation-in-part of copending application Ser. No. 792,235, filed Jan. 16, 1969, now abandoned which application is a division of application Ser. No. 621,755 filed Mar. 9, 1967, now US. Pat. No. 3,468,955, which is a division of application Ser. No. 440,311, filed Mar. 16, 1965, now US. Pat. No. 3,330,851.

This invention relates to new steroidal compounds and, more particularly, to new steroids of the A-norandrostane series, new intermediates useful in the preparation of the same, and processes for preparing the same.

The new final products of this invention are of the Formula I:

wherein Y is B-hydro-gen or B-cyano; R is hydroxy or acyloxy; and R is vinyl, ethynyl, halo substituted vinyl, trifluoromethyl substituted vinyl, halo substituted ethynyl and trifluoromethyl substituted ethynyl. Among the suitable acyloxys may be mentioned the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric, hexanoic and enanthic acid), the lower alkenoic acids, the cycloalkane carboxylic acids, the cycloalkene carboxylic acids, the monocyclic aromatic carboxylic acids (e.g., benzoic acid), and the monocyclic aryllower alkanoic acid (e.g., phenacetic and 8- phenylpropionic acid). Among the suitable halogen substituted vinyls may be mentioned perhalovinyls, such as trifluorovinyl, trichlorovinyl, 1,2-difluoro-2-chlorovinyl and 1,2-difluoro-2-bromovinyl; the dihalovinyls, such as 1,2-difluorovinyl, 2,2-difluorovinyl, l-chloro-Z-fluorovinyl, l-bromo-Z-fluorovinyl, and 1,2-dichlorovinyl; and the monohalovinyls, such as l-fiuorovinyl, 2-fiuorovinyl, 1- chlorovinyl, Z-chlorovinyl, and l-bromovinyl. Among the suitable halogen substituted ethynyls may be mentioned fluoroethynyl, chloroethynyl and bromoethylnyl.

The final products of this invention are physiologically active compounds that possess fertility inhibiting activity. Hence, they may be administered orally or parenterally in lieu of known anti-fertility agents, such as progestagens and estrogens for control of conception, the dose being adjusted for the activity of the particular compound.

The compounds of this invention are prepared by interacting a compound of the Formula II:

wherein Y is as hereinbefore defined and R" is keto or ketal, with a compound of the formula: R'X, wherein R is as hereinbefore defined, and X is an activating group such as magnesium bromide, lithium or a complex thereof (e.g., a lithium ethylenediamine complex). When Y is cyano, a 2-ketal (R" is ketal) must be used. When Y is hydrogen, either a Z-ketal or 2-ketone may be used as the reactant. Although any ketal may be used, the preferred ketals are those with alkanediols, such as ethylene glycol and propylene glycol. T 0 complete the reaction, water is then added, thereby yielding products of the Formula III:

HO R

wherein Y, R and R" are as hereinbefore defined.

If the compound of Formula III formed contains a 2-ketal group, it may be hydrolyzed, by treatment with an aqueous solution of a strong acid, such as p-tolnenesultonic acid, to yield the corresponding 2-keto derivative. If a 17-ester is desired as the final product, the compound of Formula III, in its free 2-keto form, is reacted with the acyl chloride or acid anhydride of the desired acid, preferably one of the acids mentioned hereinbefore, to yield the 17-ester.

In those instances where ketals of Formula II are used, they may be prepared by first treating either Sfi-cyano-A- nortestosterone (prepared as described in US. patent application, Ser. No. 355,913, filed Mar. 30, 1964 now US. Pat. 3,271,437) or 5B-A-norandrostane-Z-one-17(3- 01 with a ketalizing agent, such as ethylene glycol or propylene glycol, in the presence of a strong acid, such as p-toluenesulfonic acid, to yield the corresponding 2-ketal derivative; and then oxidizing such derivative, as by (III) 5 treatment with chromium oxide, to yield the corresponding 17-keto derivative.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 l7aethynyl-5,8-cyano-A-norandrostane-Z-one-175-01 Z-ethylene ketal (a) Preparation of 5,8-cy-ano-A-norandrostane-Z-one- 175-01 2-ethylene ketal 17-acetate A mixture of mg. of 5,8-cyano-A-nortestosterone and 7 mg. of p-toluenesulfonic acid is stirred and refluxed in 40 ml. of benzene and 3 ml. of ethylene glycol for one day and the water removed by a calcium carbide trap. The reaction mixture is diluted with water and-the benzene layer is separated. The aqueous layer is extracted with additional benzene The combined benzene extracts are washed with 8% salt solution and evaporated to give a residue which is acetylated by refluxing in 2 ml. of acetic anhydride containing 0.2 ml. of pyridine for one hour. The reactionmixture is PQured into ice-water and extracted with chloroform. Thechloroform extracts are washed'with a saturated. sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using a mixture of chloroform and hexane (1:2) as the developing solvent gives a major band at about Rf 0.35 which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from isopropyl ether-hexane gives about 75 mg. of fi-cyano-A-norandrostane-Z-one-17/3-01 2-ethylene ketal 17-acetate, M.P. about 175-177. The analytical sample is prepared by recrystallization from isopropyl ether-hexane, M.P. about 182.5183.5; [04 +3 (EtOH); tKBr 4.50 and 577a; TSi(CH3)4 9.20 (s., 18-Me), 8.78 (s., l9-Me), 7.97 (s., 17-acetate), and 6.13 (m., ketal methylenes).

Analysis.Calcd for C H O N (387.50) (percent): C, 71.29; H, 8.58; N, 3.61. Found (percent): C, 71.28; H, 8.59; N, 3.50.

(b) Preparation of Sfl-cyano-A-norandrostane-Z-one- 176-01 Z-ethylene ketal (i) A solution of 100 mg. of SB-cyano-A-norandrostane-2-one-17fi-ol 2-ethylene ketal 17-acetate in 1 ml. of aqueous potassium carbonate solution and 10 ml. of methanol is stirred at room temperature for 18.5 hours. The reaction mixture is diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using a mixture of chloroform and hexane (2:1) as the developing solvent gives a major band which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from isopropyl ether gives about 40 mg. of 5B cyano A norandrostane 2 one 17 3 ol 2-ethylene ketal, M.P. about 172-174. The analytical sample is prepared by recrystallization from isopropyl ether, M.P. about 175.5176.5, 6 (EtOH); xKBr 2.85 and 4.50/1.; TSi(CH 9.26 (s., 18-Me), 8.79 (s., 19-me), 6.12 (mm, ketal methylenes) and 6.38 (m., 17-H).

Analysis.-Calcd for C H O N (345.47) (percent): C, 73.00; H, 9.05. Found (percent): C, 72.92; H, 9.01.

(ii) Ketalization of SB-cyano-A-nortestosterone as described in Step (i) of this example gives rise to 5,8-cyano- A-norandrostane-12-one-178-01 2-ethylene ketal.

(c) Preparation of 5,8-cyano-A-nonandrostane-Z,17-

dione 2-ethylene ketal A solution of 50 mg. of SB-cyano-A-norandrostane-2- one-17B-ol Z-ethylene ketal in 2 ml. of acetone is treated dropwise with stirring with an equivalent amount of chromium trioxide-sulfuric acid. The reaction mixture is treated with one drop of pyridine, filtered and diluted with water. The aqueous phase is extracted with ether, The ether extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from chloroform-isopropyl ether gives about 27 mg. of Sfl-cyano-A-norandrostane- 2,17-dione 2-ethylene ketal, M.P. about 212.5- -2l3.5. The analytical sample is prepared by recrystallization from chloroform-isopropyl ether, M.P. about 213.5- 2l4.5,,[t1]1 +73 (EtOH); xKBr 4.50 and, 5.78 :rSi(CH 9.12 (s., 18-Me), 8.76 (s., 19-Me).and 6.13 (m., ketal methylenes). t

Analysis.-Calcd for C21H2903N (343.45) (percent): C, 73.43; H, 8.51; N, 4.08. Found (percent): C, 73.40; H, 8.52; N, 4.32.

'4 l (d) Preparation of 17a-ethynyl-SB-cyano-A-noraridrostane-2-one-17fl-ol 2-ethylene ketal A- mixture of 200 mg. of 5B-cyano-A-norandrostane- 2,17-dione 2-ethylene ketaland 100 mg. of lithium acety lide ethylenediamine complex in 10 ml. of benzene and 10 ml. of tetrahydrofuran under an atmosphere of helium is slowly warmed to over a one hour period and maintained at this temperature for 6 additional hours. The reaction mixture is treated with 5 ml. of water and refluxed for one hour, diluted with water and extracted with chloroform. The chloroform extracts are [washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from methanol gives 61 mg. of 17a-ethynyl-SB-cyaho-A-norandrostane-2-one-l7fl-ol 2-ethylene ketal, M.P. about 262264. The analytical sample is prepared by recrystallization from methanol-isopropyl ether, M.P. about 269270, 32 (EtOH-l-l drop pyridine); xKBr 2.92, 3.08 and 4.50

Analysis.-Calcd for C H O N (369.49) (percent): C, 74.76; H, 8.46. Found (percent): C, 74.65; H, 8.57.

EXAMPLE 2 17 a-ethynyl-5 ,8-cyanoA-norandrostane-Z-one-175-01 A mixture of 220 mg. of 17a-ethyny1-5p-cyano-A-norandrostane-2-one-17fi-ol 2-ethylene ketal and 25 mg. of p-toluenesulfonic acid in 2 ml. of Water and 20 ml. of acetone is refluxed for 22 hours, diluted with water and the acetone evaporated. The aqueous phase is extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using chloroform as the developing solvent gives a major band which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from ethyl acetate-isopropyl ether gives 112 mg. of 17a-ethyny1-5fl-cyano-A-norandrostane2-one-17,8-01, M.P. about l7417 6. The analytical sample is prepared by recrystallization from ethylacetate-petroleum ether (B.P. 30 75"), M.P. about 181.5-1825", [M 124 (EtOH); xKBr 2,93, 3.05, 4.50 and 5.72;; "'T Si(CH 9.13 (s., 19-Me), 8.61 (s., 19-Me), and 7.42 (s., 17a-ethynyl-H).

AnaIysis.Calcd for C H O N (325.43) (percent): C, 77.50; H, 8.36. Found (percent): C, 77.59; H,.8.42.

EXAMPLE 3 17ot-ethynyl-SB-cyano-A-norandrostane- 2-one-17fl-ol acetate A solution of 0.0033 ml. of perchloric acid in 0.3 m1. of acetic anhydride is added to 500 mg. of 17a-ethynyl- 5,B-cyano-A-norandrostane-Z-one-175-01 in 10 ml. of acetic anhydride. The reaction mixture is stirred at room temperature for 30 minutes and then poured into ice- Water and extracted with chloroform. The chloroform extracts are washed with a saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to dryness to give.17ot-ethyny1-5p-cyano- A-norandrostane-2-one-17/3-01 acetate.

Similarly,.by Substituting any other acyl chloride or acid anhydride for the acetic anhydride in the procedure of Example 3, the corresponding 17-ester is formed. Thus, propionic anhydride and benzoyl chloride yield the pro pionate and benzoate, respectively.

EXAMPLE 4 17a-trifluoropropynyl-5 8-cyano-A-norandrostane- 2-one-17,B-ol Z-ethylene ketal A solution of mg. of SB-cyano-A-norandrostane- 2,17-dione 2-ethylene ketal in 15 ml. of tetrahydrofuran is treated with an excess of trifluoropropynylmagnesium bromide (prepared from ethyl magnesium bromide and excess trifluoropropyne in tetrahydrofuran solution). The

reaction mixture is refluxed for 6 hours, cooled, and then treated with a saturated ammonium chloride solution and the organic layer separated. The aqueous layer is extracted with chloroform. The combined organic fractions are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17oc-t1ifluoropropynyl-55-cyano-A-norandrostane-2-one-1718-01 2- ethylene ketal.

EXAMPLE 5 17aand 17 3-chloroethyny1-Sfi-cyano-A-norandrostane-2-one-17-ols 2-ethylene ketal EXAMPLE 6 17 a-trifluorovinyl-513-cyano-A-norandrostane- 2-one-l7B-ol 2-ethylene ketal A solution of 3 mg. of 5B cyano-A-norandrostane- 2,17-dione 2-ethylene ketal in 25 m1. of tetrahydrofuran is treated with an excess of trifluorovinylmagnesium bromide (prepared from magnesium and trifluorobromoethylene in tetrahydrofuran solution). The reaction mixture is refluxed for 6 hours, cooled, and'then treated with a saturated ammonium chloride solution and the organic layer separated. The aqueous layer is extracted with chloroform. The combined organic fractions are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17vi-trifluorovinyl-S/S-cyano-A- norandrostane-Z-one-17,8-ol 2-ethy1ene ketal.

Similarly, by substituting the indicated magnesium bromide for the trifluorovinylmagnesium bromide in the procedure of Example 6, the indicated l7a-R'-5y8-cyano-A- norandrostane-Z-one-175-01'2 ethylene ketal is formed:

Example Reaetant Product R is:

7. Vinylmagnesium bromide Vinyl.

8 fl-Chlorovinyimagnesium bromide-.- fl-Chlorovmyl.

9. afl-Dichlorovimrlmagnesium a,B-Dichlorovinyl.

bromide.

EXAMPLE 11 17u-trifluoropropynyl-SB-cyano-A-norandrostane-2-one-17fi-ol ene ketal in the procedure of Example 2, the indicated R'-5,8-cyano-A-norandrostane-2-one-175-01 is formed.

Example Reactant R is: Product R is:

12 l7a-chloroethynyl l7a-chl0roethynyl. 13 176 chloroethynyll7B-chloroethynyl.

15.- 17a-fl-chlorov1nyl. 17a-fi-chlorovinyl. 16 17a-a,B-dichlorovinyl 17a-a,fl-dichloroviuyl. l7 17a-a,;3-difluor0vinyl 17a-a,B-difiuorovinyl.

EXAMPLE 18 17a-trifluoropropynyl-Sfi-cyano-A-norandrostane-2-one- 17 [3-01 acetate Following the procedure of Example 3, but substituting an equivalent amount of l7a-trifiuoropropynyl-SB-cyano-A-norandrostane-2-one-175-01 for the 17a-ethynyl- Sfl-cyano-A-norandrostane-2-one-173-01, there is obtained 17a trifluoropropynyl-Sfi-cyano-A-norandrostane-Z-onel7,B-ol acetate.

EXAMPLE 19 17ix-ethynyl-Sfi-norandrostane-Z-one-175-01 Following the procedure in Example 1, step (d), but substituting 55-A-norandrostane-2,17-dione for SB-cyano- A-norandrostane-2,17-dione 2-ethylene ketal, there is obtained 17ot-ethynyl-Sfi-A-norandrostane-Z-one-175-01, h KBr 2.91, 3.03 and 5.78;.t.

EXAMPLE 20 17a-trifiuoropropynyl-Sfl-A-norandrostane-2-one-173-01 Following the procedure in Example 4, but substituting Sfl-A-norandrostane-Z,17-dione for SB-cyane-A-norandrostane-2,l7-dione Z-ethylene ketal, there is obtained 17a-trifluoropropynyl-Sfl-A-norandrostane-Z-one--01.

EXAMPLE 21 17aand 17/3-chloroethynyl-5B-A-norandrostane- 2-one-17-ols Following the procedure in Example 5, but substituting 5,8-A-norandrostane-2,17-dione for S-cyano-A-norandrostane-2,17-dione 2-ethylene ketal, there is obtained a mixture of 17ocand 17,3-chloroethynyl-SB-A-norandrostane- 2-one-17-ols.

EXAMPLE 22 17a-triiluorovinyl-5fl-A-norandrostane-Z-one-175-01 Following the procedure in Example 6, but substituting SB-A-norandrostane-Z,17-dione for Sfi-cyano-A-norandrostane-2,17-dione 2-ethylene ketal, there is obtained 17atrifluorovinyl-5 8-A-norandrostane-2-one-175-01.

EXAMPLE 23 17a-trifluoropropenyl-5;3-A-norandrostane-2-one-175-01 Hydrogenation of 17-trifluoropropynyl-Sfl-A-norandrostane-2-one-17fi-ol at 45 psi. with Lindlar catalyst gives 17u-trifluoropropenyl-5,3-A-norandrostane-2-one.

EXAMPLE 24 17u-ethyny1-SB-A-norandrostane-2-one-17,8-01 acetate Following the procedure of Example 3, but substituting 17a-ethynyI-SB-A-norandrostane 2 one-17,3-ol for the 17u-ethynyI-Sfl-cyano-A-norandrostane-Z-one-175-01, there is obtained l7u-ethynyl-5 8- -norandrostane-2-one-17,8-01 acetate.

Similarly, the 17-free alcohols of Examples 20 through 23 can be converted to their acetate derivatives.

Following the procedure of Example 3 but substituting hexanoyl chloride for acetic anhydride there is obtained the 174! ethynyl-Sfi-cyano-A-norandro stane-2-one-175-01 hexanoate.

EXAMPLE 27 Following the procedure of Example 3 but substituting decanoyl chloride for acetic anhydride there is obtained the 1700 ethynyl 5B-cyano-A-norandrostane-Z-one-17-01 decanoate.

EXAMPLE 28 Following the procedure of Example 3 but substituting benzoyl chloride for acetic anhydride there is obtained the l7a-ethynyl-5fl-cyano-A-norandrostane-2 one 17B ol benzoate.

EXAMPLE 29 Following the procedure of Example 3 but substituting naphthoyl chloride for the acetic anhydride there is obtained the 17a-ethynyl-5(3-cyano-A-norandrostane-2-one- 175-01 naphthanoate.

EXAMPLE 30 Following the procedure of Example 3 but substituting cyclohexylcarbonyl chloride for the acetic anhydride there is obtained the 17a-ethynyl-SB-cyano-A-norandrostane-2- one-17fi-ol cyclohexylcarbonate.

EXAMPLE 3 1 Following the procedure of Example 3 but substituting cyclopentenylcarbonyl chloride for the acetic anhydride there is obtained the 17u-ethynyl-Sfl-cyanc-A-norandrostane-2-one-17fl-ol cyclopentenylcarbanoate.

EXAMPLE 32 Following the procedure of Example 3 but substituting phenylacetyl chloride for the acetic anhydride there is ob tained the 17a-ethynyl-5,B-cyano-A-norandrostane-2-one- 173-01 phenyl acetate.

EXAMPLE 33 Following the procedure of Example 3 but substituting fl-phenylpropionic acid chloride for the acetic anhydride there is obtained the 17a-ethynyl-5,3-cyano-A-norandrostane-2-one-17fl-o1 ,B-phenylpropionate.

8 What is claimed is: 1. A compound of the formula 4 W Y j v A I k /C wherein Y is selected from the group consisting of fi-hydrogen and fi-cyano; R is hydroxy or acyloxy of a hydrocarbon carboxylic acid of less than twelve carbons; R is selected from the group consisting of vinyl, ethynyl, halo substituted vinyl, trifluoromethyl substituted vinyl, halo substituted ethynyl and trifluoromethyl substituted ethynyl; and A is ethylene or propylene.

2. A compound of claim 1 having the name 17a-ethynyl- Sfi-cyano-A-norandrostane-2-one-17/8-ol-2-ethylene ketal.

3. A compound of claim 1 having the name l7a-tlifluoropropynyl-SB-cyano-A-norandrostane-2-one-1713-01 2- ethylene ketal.

4. A compound of claim 1 having the name 17tX-Ch10l'0- ethynyl-5/3-cyano-A-norandrostane-2-one 17p o1 Z-ethylene ketal.

5. A compound of claim 1 having the name 17B-chloroethynyl-Sfi-cyano-A-norandrostane-2-one-l7oc-ol 2 ethylene ketal.

6. A compound of claim 1 having the name 17oc-tlifluorovinyl-SB-cyano-A-norandrostane-Z-one 17p ol 2- ethylene ketal. V

7. A compound of claim 1 having the name SB-cyano-A- norandrostane-Z-one--01 2-ethylene ketal l7-acetate.

8. A compound of claim 1 having the name Sfi-cyano- A-norandrostane-Z-one-175-01 2-ethylene ketal.

9. A compound of claim 1 having the name 5fl-cyano A-norandrostane-Z,17-dione Z-ethylene ketal.

References Cited UNITED STATES PATENTS 3,271,437 9/1966 Levine et a1. 260-464 ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner US. Cl. X.R. 260-340], 464, 469, 176, 488, 586; 424278 2222 83 V UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 7 Patent 110. 3 647 820 Dsted March 7 1972 Inventofla) Seymour D. Levineand Patrick A. Diassi It is certified that error appears in the above-identified patent and that: said Letters Patent are hereby corrected as shown below:

F- Column 3, line 46-, (mm. should read (m.

Column 6, line 47, "5-cyano" should read 5B-cyano and on line 61, "l7-trifluoropropyny1" should read 17OL-trif1uoro propynyl Column 7, line. 17,. "17-01" should read 176- 01 Signed and sealed th1s'27th day of June 1972.

(SEAL) 'Att'est:

mum]: M.FLETCHER,JR. v ROBERT GOTTSCHA LK 'Attesting Officer v Commissioner of Patents 

